In recent years, due to westernization of food, patients with hypercholesterolemia, hypertriglyceridemia, hypo HDL cholesterolemia, or the like, which are in a category of so-called lifestyle-related diseases have been increasing. In addition, recently, patients with mixed or combined dyslipidemia with both hypercholesterolemia and hypertriglyceridemia have been increasing. Particularly, patients of mixed dyslipidemia have LDL cholesterol (LDL-C) and triglyceride (TG) raised, and have HDL cholesterol (HDL-C) lowered. Such a high TG and low HDL-C condition is observed also in patients with metabolic syndrome or diabetes. It has been proven that hyper LDL chelesterolemia, hypo HDL cholesterolemia, and hypertriglyceridemia are risk factors of a coronary artery disease (CAD), a cerebrovascular disorder, or the like. The importance of the management of dyslipidemia is described in “Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012” released by Japan Atherosclerosis Society.
Dyslipidemia, particularly hypercholesterolemia has become a disease having a quite high degree of medical satisfaction due to advent of statins. However, from results of many large-scale clinical trials, it has been found that further lowering of LDL cholesterol in blood leads to prevention of coronary artery diseases (the lower, the better). More strict lipid control has been recommended. Many patients cannot reach the intended LDL-C level in blood only with statins. Combination use of multiple pharmaceutical agents has been also required (Non-Patent Document 1).
PPAR is one of receptors belonging to a nuclear receptor family. Existence of three subtypes (α, γ, and δ) is known for this receptor (Non-Patent Document 2). Among these types, PPARα is mainly expressed in the liver. When PPARα is activated, production of apo C-III is suppressed, followed by activation of lipoprotein lipase (LPL). As a result, fat is decomposed. As PPARα agonist, for example, unsaturated fatty acids and fibrate pharmaceutical agents such as fenofibrate, bezafibrate, or gemfibrozil have been known (Non-Patent Document 3). In recent years, a compound having a stronger and more selective PPARα activating effect than a conventional fibrate pharmaceutical agent has been reported (Patent Document 1).
A cholesterol ester transfer protein (CETP) is a glycoprotein having strong hydrophobicity and having a molecular weight of 68,000 to 74,000, primarily produced in the liver and small intestine, and transfers a cholesterol ester in a high density lipoprotein (HDL) to a very low density lipoprotein (VLDL) or a low density lipoprotein (LDL). Therefore, it has been reported that a CETP inhibitor typified by Anacetrapib ([4S,5R]-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-methoxy-5′-(propan-2-yl)-4- (trifluoromethyl)[1,1′-biphenyl]-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Non-Patent Document 5), hereinafter, also referred to as compound C) or Evacetrapib (Patent Document 2) suppresses cholesterol transfer from HDL to LDL to reduce LDL-C (Non-Patent Document 4).
Under such circumstances, Patent Document 3 has made a report on a combination-drug of fibric acid derivatives and CETP inhibitors. This Patent Document describes a method for treating a cardiovascular disease, specifically describes that this combination-drug can be used for medical science, particularly for atherosclerosis, hypercholesterolemia, other coronary artery diseases, and the like in mammals. However, this Document does not describe the combination of compounds of the present invention. Furthermore, the disclosed combinations of fibric acid derivatives and CETP inhibitors do not include any specific experimental example. This Document does not disclose a pharmacological effect due to a combination of multiple pharmaceuticals.